Purpose: Laser therapy has been studied as a treatment for herpes labialis for some years. This study aimed to compare the efficacy of 660-nm low-level laser to defocused 810-nm high-power laser for treatment of herpes labialis. Methods: In this single-blinded clinical trial study, evaluated 32 patients with herpes labialis in prodromic and early vesicle phase (first 48 h) were divided into two same groups by inclusion-extrusion criteria consideration and ethic codes. For group A low-level 660-nm diode laser (6 J/cm2, 100 mW, 0 Hz, 60 s, near contact, focal point of laser unit was 1 cm2) and for group B high-power defocused 810-nm diode laser (2 W, CW, 300-µ fiber, at 0.5-cm distance, 60 s, screening method from the center toward outer for 1-cm2 area) were used. Pain score changes, time of pain relief, lesion size changes, time of clinical healing, recurrence rate within 6 months, and the recurrence interval were recorded. Data were analyzed using the t-test, Chi-square test, Mann–Whitney test, and ANOVA. Results: The pain intensity significantly decreased in both groups (P < 0.001) with no significant difference between them (P = 0.14). The time of pain relief was significantly shorter in group B (P = 0.003). The difference for the size of the lesion (P = 0.6) and time of clinical healing (P = 0.21) were not significant. The reduction in frequency of recurrence was not significantly different between the two groups (P = 0.55). The mean recurrence interval was significantly longer in group B (P = 0.002). Conclusion: Two treatment methods had similar effects, but the defocused 810-nm high-power laser had better efficacy for shorter time of pain relief and longer recurrence interval in treatment of herpes labialis in this study. © 2022, The Author(s), under exclusive licence to Springer Nature Switzerland AG.